Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma

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- There are no established treatments for people with certain advanced kidney cancers. These tumors often don t respond well to currently available treatments. Researchers believe that two drugs that treat other diseases metformin and vandetanib could help people with advanced kidney cancer.

Objective:

- To test the combination of metformin and vandetanib in people with advanced kidney cancer. Phase I of the study will determine a safe dose for the drugs. Phase II will test this dose in people with certain kidney cancers.

The management of advanced renal cell carcinoma (RCC) continues to remain a challenge, particularly for patients with papillary and non-clear cell variants of RCC, for whom there is no standard therapy of proven benefit.

Inactivation of the Krebs cycle enzyme Fumarate Hydratase (FH) in tumors associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) results in a metabolic shift characterized by a) reliance on aerobic glycolysis for energy production, b) upregulation of HIF 1- and its downstream targets that promote glucose delivery and uptake to fuel aerobic glycolysis, and c) downregulation of AMPK, resulting in activation of the mTOR pathway and increased macromolecule synthesis.

Inactivation of another Krebs cycle enzyme, Succinate Dehydrogenase (SDH), is also associated with a familial form of kidney cancer which shares some of the above metabolic features.

Vandetanib is a dual VEGFR/EGFR inhibitor that reverses the metabolic phenotype associated with FH (and SDH) inactivation and has potent preclinical activity in FH-/- and SDH -/- tumors. Metformin activates AMPK and has demonstrated potent synergy when combined with vandetanib, in preclinical models of FH -/- tumors.

In this phase 1/2 trial, we first propose to establish the safety and dosing parameters of combined vandetanib and metformin therapy. We then propose to test the activity of vandetanib in combination with metformin in patients with HLRCC or SDH-associated RCC, as well as those with sporadic forms of papillary RCC.

OBJECTIVE:

Phase I Component:

-Establish the safety and maximum tolerated dose of the combination of vandetanib with metformin in patients with advanced RCC.

Brain metastases or spinal cord compression that requires treatment, unless the treatment ended at least 4 weeks before starting protocol therapy and the condition has been stable without steroid treatment for at least 10 days

No major surgery within four weeks or inadequately healed wounds prior to study enrollment

Adequate organ function

DESIGN:

Phase I Component:

Combination vandetanib and metformin will be administered at starting doses of 300 mg QD and 250 mg BID, respectively.

The study design is based on a single arm, fixed order dose-escalation Phase 1 study using a modified Fibronacci schema.

Up to 6 patients may be enrolled in a specific dose combination cohort. Based on the assumption that 3 dose levels will be evaluated, the total number of evaluable patients will be 18. To allow for a few patients who may be inevaluable, the accrual ceiling for this portion of the study will be set at 21. Based on how dose escalation proceeds and the adverse events seen, the total number of patients to be accrued may be changed via a protocol amendment.

Phase II Component:

Once the MTD is determined, the appropriate combination dose will be evaluated in the phase 2 component.

Patients will be accrued into one of two independent, parallel cohorts:

Phase 1 Component: To establish the safety and maximum tolerated dose (MTD) of vandetanib and metformin when used in combination in patients with metastatic RCC. [ Time Frame: 1- 2 years ]

Phase 2 Component: To determine the overall response rate (RECIST 1.1) following treatment with the combination of vandetanib and metformin in patients with 1) advanced RCC associated with HLRCC or SDH, and 2) advanced sporadic/non-HLRCC papilla... [ Time Frame: 2- 3 years ]

Secondary Outcome Measures
:

Phase 1 Component: Evaluate the clinical activity of the combination of vandetanib and metformin [ Time Frame: 2-3 years ]

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Ages Eligible for Study:

18 Years to 100 Years (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

INCLUSION CRITERIA:

Diagnosis/Histology

Phase I Component Histologically confirmed advanced RCC of any subtype.

Phase 2: Patients must have measurable disease based on RECIST 1.1 criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan or MRI (except for lymph nodes, which must be >15 mm).

3. Prior Therapy

Phase 1- Patients with clear cell RCC must have either declined, be ineligible to receive, have progressed on, or be intolerant to high dose IL-2, or standard first and second line VEGF, or mTOR targeted agents. As there is no standard therapy for metastatic non-clear cell RCC, no prior therapy is required.

Phase 2- No more than two prior VEGF-pathway targeted agents

No previous treatment with vandetanib. Previous or ongoing treatment with metformin is allowed.

7. Patients must have normal organ and marrow function as defined below:

absolute neutrophil count greater than or equal to 1,500/mcL

platelets greater than or equal to 100,000/mcL

total bilirubin less than or equal to 1.5x upper limit of reference range ( < 3x upper limit of reference range in patients with Gilbert s disease)

AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal

eGFR (CKD-EPI) greater than or equal to 50 mL/min/1.73 m2

8. Men and women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for at least 6 months after vandetanib/metformin therapy. Should a woman become pregnant (either a participant or the partner of a male participant) or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.

9. Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Known serious allergic reaction to vandetanib or metformin.

Brain metastases or spinal cord compression that requires treatment, unless the treatment ended at least 4 weeks before starting protocol therapy and the condition has been stable without steroid treatment for at least 10 days.

Major surgery (includes any surgery that carries significant risk of blood loss, extended periods of general anesthesia, or requires at least an overnight hospital admission) within 28 days before starting treatment or inadequately healed incision/scar from prior surgery.

Any unresolved chronic toxicity greater than Common Terminology Criteria for Adverse Event (CTCAE) Grade 2 or greater from previous anti-cancer therapy (this criterion does not apply to alopecia).

Significant cardiac event (eg, myocardial infarction), New York Heart Association (NYHA) classification of heart disease greater than or equal to 2 within 12 weeks before starting treatment, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia.

Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.

Previous or current invasive malignancies of other histologies requiring treatment within the last 2 years, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin (phase 2 only).

13 Congenital long QT syndrome.

14 Any concomitant medications that are known to be associated with Torsades de Pointes Drugs that in the investigator s opinion cannot be discontinued, are allowed however, must be monitored closely

16 History of QT prolongation associated with other medications that required discontinuation of that medication.

17 QTcF correction unmeasurable or >450 ms on screening ECG (Note: If a patient has a QTcF interval >450 ms on screening ECG, the screening ECG may be repeated twice [at least 24 hours apart] for a total of 3 ECGs. The average QTcF from the three

screening ECGs must be less than or equal to 450 ms in order for the patient to be eligible for the study).

18. Women that are currently breast feeding.

19. Active treatment-refractory diarrhea that may affect the ability of the patient to absorb the trial agents or tolerate further diarrhea.

20. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with vandetanib/metformin.